Bottom Line:
Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo.The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis.Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.

Affiliation: Department of Obstetrics and Gynecology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.

ABSTRACTLysophosphatidic acid (LPA) is a bioactive lipid that enhances ovarian cancer cell proliferation, migration and invasion in vitro and stimulates peritoneal metastasis in vivo. LPA is generated through the action of autotaxin or phospholipases, and degradation begins with lipid phosphate phosphohydrolase (LPP)-dependent removal of the phosphate. While the effects of LPA on ovarian cancer progression are clear, the effects of LPA metabolism within the tumor microenvironment on peritoneal metastasis have not been reported. We examined the contribution of lipid phosphatase activity to ovarian cancer peritoneal metastasis using mice deficient in LPP1 expression. Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo. Within 2 weeks of intraperitoneal injection of syngeneic mouse ovarian cancer cells, we observed enhanced tumor seeding in the LPP1 KO mice compared to wild type. However, tumor growth plateaued in the LPP1 KO mice by 3 weeks while tumors continued to grow in wild type mice. The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis. Tumor growth was restored and apoptosis reversed with exogenous administration of LPA. Together, these observations demonstrate that the elevated levels of LPA per se in LPP1 KO mice do not inhibit tumor growth. Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.

Mentions:
While the contribution of LPA to ovarian cancer growth and progression has been studied extensively [1,2,4,7–11], the effects of LPA metabolism on cancer progression are poorly understood. We investigated the effect of reduced LPA turnover on metastatic peritoneal ovarian cancer growth and progression using mice lacking the lipid phosphatase, LPP1 (LPP1 KO) and a syngeneic mouse ovarian cancer cell line, ID8ip2Luc. In vivo imaging of mice following intraperitoneal (IP) injection of ID8ip2Luc cells revealed increased luminescence in LPP1 KO mice compared to wild type within 2 weeks (Fig. 1A). Physical examination of the peritoneal cavity upon necropsy 2 weeks after tumor initiation showed no indication of tumor nodules (data not shown) and no difference in weights of the omentum (primary site of tumor metastasis) between genotypes (S1 Fig.) or from non-tumor bearing mice (data not shown). However, evaluation of H&E stained sections of the omentum revealed the presence of microscopic tumor nodules (S1 Fig.), consistent with previous observations [26]. Importantly, significantly more microscopic nodules were observed in omentums from LPP1 KO mice compared to wild type (Fig. 1B). Furthermore, LPP1 KO mice were more likely to harbor invasive lesions (Fig. 1C, S1 Fig.) that coincided with mesothelial VCAM-1 expression (Fig. 1D, S1 Fig.), which promotes tumor invasion of the mesothelium [26]. Together, these observations indicate that loss of LPP1 in the tumor microenvironment facilitates tumor seeding and mesothelial invasion of the peritoneal cavity.

Bottom Line:
Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo.The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis.Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.

Affiliation:
Department of Obstetrics and Gynecology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.

ABSTRACTLysophosphatidic acid (LPA) is a bioactive lipid that enhances ovarian cancer cell proliferation, migration and invasion in vitro and stimulates peritoneal metastasis in vivo. LPA is generated through the action of autotaxin or phospholipases, and degradation begins with lipid phosphate phosphohydrolase (LPP)-dependent removal of the phosphate. While the effects of LPA on ovarian cancer progression are clear, the effects of LPA metabolism within the tumor microenvironment on peritoneal metastasis have not been reported. We examined the contribution of lipid phosphatase activity to ovarian cancer peritoneal metastasis using mice deficient in LPP1 expression. Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo. Within 2 weeks of intraperitoneal injection of syngeneic mouse ovarian cancer cells, we observed enhanced tumor seeding in the LPP1 KO mice compared to wild type. However, tumor growth plateaued in the LPP1 KO mice by 3 weeks while tumors continued to grow in wild type mice. The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis. Tumor growth was restored and apoptosis reversed with exogenous administration of LPA. Together, these observations demonstrate that the elevated levels of LPA per se in LPP1 KO mice do not inhibit tumor growth. Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.